DESCRIPTION: Interferon-gamma (IFN-gamma) is a cytokine produced in response to some microbial infections, that has widespread effects throughout the body. It influences the development and differentiation of cells involved in immune responses and regulates the expression of activation, adhesion, and major histocompatibility (MHC) molecules on many cell types. Several studies have implicated IFN-gamma in the pathology of central nervous system (CNS) demyelinating diseases, such as multiple sclerosis (MS). To address the effects of persistent expression of IFN-gamma in selected regions of the CNS, Dr Evans generated transgenic mice that express murine IFN-gamma in oligodendrocytes in the CNS. Expression of the transgene began after eight weeks of age, and resulted in primary axonal demyelination throughout the CNS accompanied by weight loss, weakness, and premature death. Dr Evans' results demonstrated that IFN-gamma can induce CNS demyelination leading to clinical disease. This proposal addresses the mechanisms by which IFN-gamma induces CNS demyelination, and the effects of constitutive CNS expression of IFN-gamma on models of CNS autoimmune disease. The first Specific Aim tests the hypothesis that IFN-gamma-induced demyelination occurs indirectly by influencing the expression of other cytokine and/or MHC gene expression in the CNS. The second Aim tests the hypothesis that expression of IFN-gamma in the CNS induces the synthesis of nitric oxide, which is toxic to myelin. The third Aim addresses the hypothesis that the expression of IFN-gamma in the CNS leads to increased susceptibility to autoimmune disease in the CNS. The effect of IFN-gamma on the course of two experimentally-induced autoimmune diseases will be evaluated. The long-term objectives of this application are to define the roles of IFN-gamma in CNS demyelination and autoimmunity. The ultimate goals are an understanding of the mechanism of demyelination in MS, and the design of therapies to treat and prevent this disease.